1. Field of the Invention
The present invention relates to a medicament for treating a patient who cannot be cured with a medicament comprising as an active ingredient an antibody composition produced by a cell unresistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α-bond in a complex N-glycoside-linked sugar chain, and a method for screening the patient by using the medicament.
2. Brief Description of the Background Art
Since antibodies have high binding activity, binding specificity and high stability in blood, their applications to diagnosis, prevention and treatment of various human diseases have been attempted [Monoclonal Antibodies: Principles and Applications, Wiley-Liss, Inc., Chapter 2.1 (1995)]. Also, production of a humanized antibody such as a human chimeric antibody or a human complementarity determining region (hereinafter referred to as “CDR”)-grafted antibody from a non-human animal antibody have been attempted by using genetic recombination techniques. The human chimeric antibody is an antibody in which its antibody variable region (hereinafter referred to as “V region”) is derived from a non-human animal antibody and its constant region (hereinafter referred to as “C region”) is derived from a human antibody. The human CDR-grafted antibody is an antibody in which the CDR of a human antibody is replaced by CDR derived from a non-human animal antibody.
It has been found that five classes, IgM, IgD, IgG, IgA and IgE, are present in mammal antibodies. Antibodies of human IgG class are mainly used for the diagnosis, prevention and treatment of various human diseases because they have functional characteristics such as long half-life in blood and various effector functions [Monoclonal Antibodies: Principles and Applications, Wiley-Liss, Inc., Chapter 1 (1995)]. The human IgG class antibody is further classified into the following 4 subclasses: IgG1, IgG2, IgG3 and IgG4. A large number of studies have so far been conducted for antibody-dependent cell-mediated cytotoxic activity (hereinafter referred to as “ADCC activity”) and complement-dependent cytotoxic activity (hereinafter referred to as “CDC activity”) as effector functions of the IgG class antibody, and it has been reported that among antibodies of the human IgG class, the IgG1 subclass has the highest ADCC activity and CDC activity [Chemical Immunology, 65, 88 (1997)]. In view of the above, most of the anti-tumor humanized antibodies, including commercially available an anti-CD20 antibody RITUXAN (Rituximab) (manufactured by IDEC/Genentech) and an anti-HER2 antibody HERCEPTIN (manufactured by Roche/Genentech), which require high effector functions for the expression of their effects, are antibodies of the human IgG1 subclass.
Also, ills known that the degrees of ADCC activity and CDC activity show a positive correlation to the expressed amount of antigens on target cells [J. Immunol., 116, 253 (1976), J. Natl. Cancer Inst., 72, 673 (1984), J. Nucl. Med., 27, 422 (1986), Cancer Res., 48, 6303 (1988), British J. Cancer, 78, 478 (1998)]. Also, it has been proved by examinations using Herceptin that commercially available therapeutic antibodies do not show their therapeutic effects unless an antigen amount at a certain degree is present on target cells.
That is, as a result of analysis on the correlation between the ADCC activity of HERCEPTIN and the expressed amount of HER2 antigen on target cancer cells, it was shown that the ADCC activity is hardly induced when the number of HER2 on the target cell is at the level of 104, that significant ADCC activity is induced when the number of HER2 on the target cell is at the level of 105 or more, and that high ADCC activity is induced when the number of HER2 on the target cell is at the level of about 106. For example, HERCEPTIN shows high ADCC activity upon a human breast cancer cell line SK-BR-3 expressing 9.0×105 of BER2 molecules, but HERCEPTIN did not exert ADCC activity upon a human breast cancer cell line MCF7 expressing 2.2×104 of HER2 molecules [Cancer Immunol. Immunother., 37, 255 (1993), HERCEPTIN injection 150 pamphlet, HER.PA.1.2 (June, 2001)].
Also, in clinical tests, it is known that therapeutic effect of HERCEPTIN is significantly high for patients recognized to have high expression of tumor tissue BFR2 by an immunohistochemistry method or a fluorescence in situ hybridization method, rather than for patients having low HER2 expression [Proc. Am. Soci. Clin. Oncol., 20, 22a (2001)]. Thus, since its therapeutic effect is hardly shown for patients having low HER2 expression, application of HERCEPTIN is limited to patients having BER2 over-expression.
In addition to HERCEPTIN, an anti-CD20 antibody RITUXAN, an anti-CD52 antibody CAMPATH and the like are known as therapeutic antibodies. All of these antibodies aim at obtaining their therapeutic effects by destroying target cells, and the ADCC activity is considered to be the major mechanism in each case. The number of antigen molecules on the treatable target cell of these antibodies is 1 to 3×105 in CD20 [J. Olin. Pathol., 51, 364 (1998)] and is also 1 to 5×105 in CD52 [Seminars in Oncology, 26 (5 Suppl 14), 52 (1999)], each requiring 105 or more. Thus, the therapeutic antibodies so far known require that an antigen is expressed at 105 or more on the target cell for the expression of ADCC activity, and no therapeutic agent which uses, as an active ingredient, an antibody for a target cell which expresses an antigen at an amount of less than 105 is known.